Direct Oral Anticoagulants versus Warfarin in Patients with Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials with Interaction Testing by Age and Sex

Background: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation (AF). Meta-analyses using individual patient data offer significant advantages over study-level data. Methods: We used individual patient data from the COMBINE AF database, which includes all patients randomized in the 4 pivotal trials of DOACs vs warfarin in AF (RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (95% CIs) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex. Results: A total of 71,683 patients were included (29,362 on standard-dose DOAC, 13,049 on lower-dose DOAC, 29,272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke/systemic embolism (883/29312 [3.01%] vs 1080/29229 [3.69%]; HR 0.81, 95% CI 0.74-0.89), death (2276/29312 [7.76%] vs 2460/29229 [8.42%]; HR 0.92, 95% CI 0.87-0.97) and intracranial bleeding (184/29270 [0.63%] vs 409/29187 [1.40%]; HR 0.45, 95% CI 0.37-0.56), but no statistically different hazard of major bleeding (1479/29270 [5.05%] vs 1733/29187 [5.94%]; HR 0.86, 95% CI 0.74-1.01), whereas lower-dose DOACs were associated with no statistically different hazard of stroke/systemic embolism (531/13049 [3.96%] vs 1080/29229 [3.69%]; HR 1.06, 95% CI 0.95-1.19) but a lower hazard of intracranial bleeding (55/12985 [0.42%] vs 409/29187 [1.40%]; HR 0.28, 95% CI 0.21-0.37), death (1082/13049 [8.29%] vs 2460/29229 [8.42%]; HR 0.90, 95% CI 0.83-0.97), and major bleeding (564/12985 [4.34%] vs 1733/29187 [5.94%]; HR 0.63, 95% CI 0.45-0.88). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke/systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (p=0.01) and lower creatinine clearance (p=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (p=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction p=0.02) and lower-dose DOACs (interaction p=0.01) versus warfarin. Conclusions: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with AF.

Screening vs no screening for preterm delivery in low risk singleton pregnancies

Introduction: To compare the effect of a policy of screening for spontaneous preterm delivery (SPD) by transvaginal cervical length (CL) measurement versus a no screening policy in the prevention of severe prematurity. Methods: Retrospective study on low risk singleton pregnancies examined at 20-24 weeks. Two cohorts one with SPD screening and the other without screening were matched using propensity analysis to create the study groups. Women with short CL were treated with vaginal progesterone and/or cervical cerclage/pessary. The outcomes examined were SPD<32 weeks (SPD 32) and SPD between 20 and 32 weeks (SPD 20-32). Results: Screening for SPD was associated with a significant reduction in the rate of SPD at less than 32 weeks (0.3% vs 0.8%, p=0.001 in the screened and no screened pregnancies respectively) and in the rate of SPD 20-32 (0.3% vs 0.9%, p=0.005 in the screened and no screened pregnancies respectively). After adjusting for maternal age, parity, body mass index, smoking and mode of conception, the screening group had significantly lower hazard for SPD 20-32 (HR=0.36, 95% CI: 0.18-0.75, p=0.006) and SPD32 (HR=0.39, 95% CI: 0.19-0.82, p=0.013). Conclusion: Screening for SPD by transvaginal CL measurement in mid pregnancy may reduce the incidence of severe prematurity in low risk singleton pregnancies.

Risk of hospitalization and mortality after breakthrough SARS-CoV-2 infection by vaccine type and previous SARS-CoV-2 infection utilizing medical claims data

We compare the risks of hospitalization (n=1121) and mortality (n=138) in a cohort of 17,881 breakthrough SARS-CoV-2 infections for the Pfizer, Moderna and Janssen vaccines for those with and without SARS-CoV-2 infections prior to vaccination. Cox regression analysis results in a lower hazard ratio for those receiving the Moderna vaccine, but a significantly higher hazard ratio for those receiving the Janssen vaccine, as compared to those who got the Pfizer vaccine. Importantly, the risk of hospitalization (P<0.001) and death (P<0.05) were lower among individuals who had a SARS-CoV-2 infection prior to vaccination, independent of age, sex, comorbidities, and vaccine type.

Association of Physical Activity with the Incidence of Atrial Fibrillation in Persons >65 Years Old: The Atherosclerosis Risk In Communities (ARIC) Study

ABSTRACTBackgroundThough moderate levels of physical activity (PA) seem to reduce the risk of atrial fibrillation (AF), the association of PA with AF in the elderly remains unclear.MethodsWe studied 5,166 participants of the Atherosclerosis Risk in Communities (ARIC) cohort that took part in visit 5 (2011-2013), were free of AF and had complete information on all variables. Self-reported PA was evaluated with a validated questionnaire and weekly minutes of leisure-time moderate to vigorous physical activity (MVPA) were calculated and categorized using the 2018 Physical Activity Guidelines for Americans (no activity [0 min/week], low [>0-<150 min/week], adequate [150-<300 min/week], high [≥300 min/week]). Incident AF between the visit 5 and the end of 2019 was ascertained from hospital discharges and death certificates. Cox models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for AF by levels of physical activity adjusting for potential confounders.ResultsThe mean (SD) age for the sample was 75 (5) years; 59% were female and 22% were Black. During a mean (SD) follow-up time of 6.3 (2.0) years, 703 AF events were identified. The association of MVPA with AF incidence showed a U-shaped relationship. Compared to those not engaging in MVPA, individuals with low MVPA had a 23% lower hazard of AF (HR= 0.77; 95% CI: 0.61, 0.96), while those with adequate MVPA had a 14% lower hazard (HR 0.86; 95% CI: 0.69, 1.06). High levels of MVPA were not associated with AF risk (HR 0.97; 95% CI: 0.78, 1.20). There was no evidence of heterogeneity when stratified by race and sex.ConclusionThis study suggests that being involved in low to moderate levels of MVPA was associated with a reduced hazard of AF. There was no evidence of increased risk of AF in those with higher levels of MVPA.

Joint Modeling of Longitudinal Ordinal Data on Quality of Life and Survival

<p>Joint models for longitudinal and survival data have been widely discussed in the literature. This thesis proposes a joint model using a stereotype model for the longitudinal ordinal responses and a Cox proportional hazards model for survival time. Our current joint model has a new feature since no literature has examined the joint model under the stereotype model. The stereotype model can improve the fit by adding extra score parameters, but it still has the advantage of requiring only a single parameter to describe the effect of a predictor on the item response levels. We give an example to model longitudinal ordinal data and survival data for patients being followed up after treatments. The main focus is on modeling both the quality of life data and the survival data simultaneously with a goal of understanding the association between the two processes over time. These two models are linked through a latent variable that characterizes the quality of life of an individual and is assumed to underlie the hazard rate. In other words, the latent variable serves as a shared variable in the joint model. We present the joint model in two different aspects: one based on a Bayesian approach and the other one a semiparametric approach using the EM algorithm. For the Bayesian approach, the latent variable is treated as a continuous variable and is assumed to have a multivariate normal distribution. The partial survival likelihood function is used in the survival component of the Bayesian joint model, while the full likelihood function is considered in the semiparametric joint model. In the latter approach the baseline hazard is assumed to be a step function and has no parametric form. The latent variable in the semiparametric joint model is then treated as a discrete variable. We illustrate our methodologies by analyzing data from the Staccato study, a randomized trial to compare two treatment methods, for Human Immunodeficiency Virus (HIV) infection of Thai patients on Highly Active Antiretroviral Therapy (HAART), in which the quality of life was assessed with a HIV Medical Outcome Study (MOS-HIV) questionnaire. Furthermore, we extend the study further to the case of multiple failure types in the survival component. Thus, the extension of the joint model consists of the stereotype model and the competing risks model. The Bayesian method is employed to estimate all unknown parameters in this extended joint model. The results we obtained are consistent for both the Bayesian joint model and the semiparametric joint model. Both models show that patients who had a better quality of life were associated with a lower hazard of HIV progression. Patients on continuous treatment also had a lower hazard of HIV progression compared with patients on CD4-guided interruption treatment.</p>

Joint Modeling of Longitudinal Ordinal Data on Quality of Life and Survival

<p>Joint models for longitudinal and survival data have been widely discussed in the literature. This thesis proposes a joint model using a stereotype model for the longitudinal ordinal responses and a Cox proportional hazards model for survival time. Our current joint model has a new feature since no literature has examined the joint model under the stereotype model. The stereotype model can improve the fit by adding extra score parameters, but it still has the advantage of requiring only a single parameter to describe the effect of a predictor on the item response levels. We give an example to model longitudinal ordinal data and survival data for patients being followed up after treatments. The main focus is on modeling both the quality of life data and the survival data simultaneously with a goal of understanding the association between the two processes over time. These two models are linked through a latent variable that characterizes the quality of life of an individual and is assumed to underlie the hazard rate. In other words, the latent variable serves as a shared variable in the joint model. We present the joint model in two different aspects: one based on a Bayesian approach and the other one a semiparametric approach using the EM algorithm. For the Bayesian approach, the latent variable is treated as a continuous variable and is assumed to have a multivariate normal distribution. The partial survival likelihood function is used in the survival component of the Bayesian joint model, while the full likelihood function is considered in the semiparametric joint model. In the latter approach the baseline hazard is assumed to be a step function and has no parametric form. The latent variable in the semiparametric joint model is then treated as a discrete variable. We illustrate our methodologies by analyzing data from the Staccato study, a randomized trial to compare two treatment methods, for Human Immunodeficiency Virus (HIV) infection of Thai patients on Highly Active Antiretroviral Therapy (HAART), in which the quality of life was assessed with a HIV Medical Outcome Study (MOS-HIV) questionnaire. Furthermore, we extend the study further to the case of multiple failure types in the survival component. Thus, the extension of the joint model consists of the stereotype model and the competing risks model. The Bayesian method is employed to estimate all unknown parameters in this extended joint model. The results we obtained are consistent for both the Bayesian joint model and the semiparametric joint model. Both models show that patients who had a better quality of life were associated with a lower hazard of HIV progression. Patients on continuous treatment also had a lower hazard of HIV progression compared with patients on CD4-guided interruption treatment.</p>

Analysis of Survival Gains in Myelodysplastic Syndromes after a Decade of the Modern Treatment Paradigm

Introduction: The treatment of myelodysplastic syndromes (MDS) changed after the approval of lenalidomide in 2005, and 2 hypomethylating agents (HMA): azacitidine in 2004 and decitabine in 2006. Erythropoietin-stimulating agents (ESA) and reduced intensity conditioning stem cell transplantation (RIC-SCT) also became more widely utilized around that period. Analyses evaluating potential overall survival (OS) improvements in MDS since 2007 across different cancer registries have shown conflicting results. 'Real-world' survival trends are important to measure the true impact of these treatments outside clinical trials, especially as MDS treatment innovations may not reach all patients. We assessed the temporal change in OS and cancer-specific survival (CSS) of MDS patients in the US over the decade before (2001 - 2006) and after modern treatment options were established (2007 - 2016). Methods: Adult subjects diagnosed with MDS between 2001 and 2016 were identified in Surveillance, Epidemiology, and End Results (SEER), and categorized in 2 groups based on year of diagnosis: 2001 - 2006 (cohort 1) and 2007 - 2016 (cohort 2). MDS histologic risk was classified into low, intermediate, and high, using International Classification of Diseases for Oncology 3 rd Edition (ICD-O-3) codes. Cause of death (COD) reported to State registries (SEER recode) was used to determine CSS, defined as death from MDS or acute myeloid leukemia. Only cases with histologic confirmation of ICD-O-3 codes and complete follow up records were analyzed. Kaplan-Meier estimation was used to summarize unadjusted OS distribution. To assess the association of cohort 2 with OS and CSS gains, follow up duration was restricted to a maximum of 5 years in both cohorts and survival analysis was performed using multivariable Cox-proportional hazards regression model adjusting for age, sex, race, ethnicity, MDS risk, and geographic location. Results: We included a total of 42,217 patients with MDS, 13,633 (30.8%) in Cohort 1 (2001 - 2006) and 30,584 (69.2%) in Cohort 2 (modern treatment era). Subjects in cohort 2 were slightly older (mean age 73.8 vs 73.2 years, p&lt;0.001) and included more males (58.6% vs 56.3%, p&lt;0.001). Cohort 1 included more subjects with low MDS histologic risk (27.8% vs 17.2%) and fewer subjects with high MDS risk (18.4% vs 20.5%) (Table 1). Median OS for low, intermediate, and high risk MDS were 44 months (95%CI, 41.5 - 46.5), 27 months (95%CI, 25.7 - 28.3) and 10 months (95%CI, 9.3 - 10.7) in cohort 1, and 48 months (95%CI 45.9 - 50.1), 26 months (95%CI 25.3 - 26.7) and 11 months (95%CI 10.6 - 11.4) in cohort 2, but these differences were not significant. In the multivariable model adjusted for age, sex, race, ethnicity, MDS risk, and geographic location, cohort 2 was associated with a significantly lower hazard of overall death compared to cohort 1, HR for OS of 0.97 (95%CI, 0.95 - 0.99, p&lt;0.001). Similarly, the modern era of treatment was associated with lower cancer-specific death compared to cohort 1, HR for CCS 0.93 (95%CI, 0.89 - 0.93, p=0.038). MDS histologic risk was the strongest factor associated with higher risk of overall and cancer-specific death. Other factors significantly associated with worse OS and CSS were advancing age, male sex, Hispanic ethnicity and unmarried status (Table 2). When analysis was restricted to patients with high risk MDS, cohort 2 was associated with a lower hazard of cancer-specific death, HR for CSS 0.90 (95%CI, 0.84 - 0.94, p=0.006), but no significant difference in overall death, HR for OS 0.96 (95%CI, 0.91 - 1.02, p=0.17). Discussion: In a SEER analysis, we found that the modern paradigm of MDS treatment, including access to lenalidomide, HMA, ESA and RIC-SCT, is associated with only modest survival gains at the population level. Across all MDS risk groups, improvements in cancer-specific death were larger than those seen for overall death and, in high risk MDS, a significant gain in CSS did not translate into longer OS. These data suggest there is a need for targeting non-cancer excess mortality in patients with MDS, who usually present with a high comorbidity burden. Strategies to optimize medical conditions coexisting with MDS and better supportive care may help consolidate the gains associated with currently available MDS-directed therapies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Association between ADCY9 Gene Polymorphisms and Ritodrine Treatment Outcomes in Patients with Preterm Labor

The purpose of this study was to investigate the genetic effects of ADCY9 on ritodrine responses in patients with preterm labor. Five single nucleotide polymorphisms (SNPs) of the ADYC9 gene in 163 patients in preterm labor were genotyped: rs879619, rs2601796, rs2531988, rs2531995, and rs2230739. Additionally, rs598961 of the PDE4B gene and rs1042719 of the ADRB2 gene were included for analysis. Patients with CC genotype of ADCY9 rs879619 had a 2.0-fold (95% confidence interval [CI]: 1.3, 3.2) higher hazard of time to delivery than T allele carriers. Patients with combined genotypes of CC in ADCY9 rs879619, AA in PDE4B rs598961, and GC, CC in ADRB2 rs1042719 showed a greater hazard of time to delivery than patients with other combinations (adjusted hazard ratio [AHR] 3.2; 95% CI: 1.7, 6.3), whereas patients carrying the C allele of ADCY9 rs2531995, G allele of PDE4B rs598961, and GG genotype of ADRB2 rs1042719 had a lower hazard of time to delivery than patients carrying other genotypes (AHR 0.4; 95% CI: 0.2, 0.7). Regarding ritodrine-induced adverse drug events (ADEs), height less than 160 cm and CC genotype of ADCY9 rs2531995 showed a greater risk of ADEs. The results of our study suggest that ADCY9 polymorphisms could affect the efficacy and safety of β2-adrenergic agonists.

Indirect comparison of tisagenlecleucel and blinatumomab in pediatric relapsed/refractory acute lymphoblastic leukemia

In the absence of head-to-head trials, an indirect-treatment comparison can estimate the treatment effect of tisagenlecleucel in comparison with blinatumomab on rates of complete remission (CR) and overall survival (OS) in patients with relapsed or primary refractory (R/R) acute lymphoblastic leukemia (ALL). Patient-level data from two pivotal trials, ELIANA (tisagenlecleucel; n = 79) and MT103-205 (blinatumomab; n = 70), were used in comparisons of CR and OS, controlling for cross-trial difference in available patient characteristics. Five different adjustment approaches were implemented: stabilized inverse probability of treatment weight (sIPTW); trimmed sIPTW; stratification by propensity score quintiles; adjustment for prognostic factors; and adjustment for both prognostic factors and propensity score. Comparative analyses indicate that treatment with tisagenlecleucel was associated with a statistically significant higher likelihood of achieving CR and lower hazard of death than treatment with blinatumomab. The tisagenlecleucel group exhibited a higher likelihood of CR than the blinatumomab group in every analysis regardless of adjustment approach (odds ratios: 6.71-9.76). Tisagenlecleucel was also associated with a lower hazard of death than blinatumomab in every analysis, ranging from 68% to 74% lower hazard of death than with blinatumomab, determined using multiple adjustment approaches (hazard ratios: 0.26-0.32). These findings support the growing body of clinical trial and real-world evidence demonstrating that tisagenlecleucel is an important treatment option for children and young adults with R/R ALL.

The best solution down the line: an observational study on taurolidine- versus citrate-based lock solutions for central venous catheters in hemodialysis patients

Introduction To prevent infection and thrombosis of central venous catheters (CVCs) in hemodialysis patients, different CVC lock solutions are available. Taurolidine-based solutions and citrate in different concentrations are frequently used, but no definite conclusions with regard to superiority have been drawn. Methods In this retrospective, observational, multicenter study, we aimed to assess the risk for removal of CVC due to infection or catheter malfunction in hemodialysis patients with CVC access for different lock solutions: taurolidine, high-concentrated citrate (46.7%) and low-concentrated citrate (4 or 30%). A multivariable Cox-regression model was used to calculate hazard ratio’s (HR). Results We identified 1514 patients (median age 65 years, 59% male). In 96 (6%) taurolidine-based lock solutions were used. In 1418 (94%) citrate-based lock solutions were used (high-concentrated 73%, low-concentrated 20%). Taurolidine-based lock solutions were associated with a significantly lower hazard for removal of CVC due to infection or malfunction combined (HR 0.34, 95% CI 0.19–0.64), and for removal of CVC due to infection or malfunction separately (HR 0.36, 95% CI 0.15–0.88 and HR0.33, 95% CI 0.14–0.79). High-concentrated citrate lock solutions were not associated with a decreased hazard for our outcomes, compared to low-concentrated citrate lock solutions. Conclusion Removal of CVC due to infection or catheter malfunction occurred less often with taurolidine-based lock solutions. We present the largest cohort comparing taurolidine- and citrate-based lock solutions yet. However, due to the retrospective observational nature of this study, conclusions with regard to superiority should be drawn with caution.